Zhang Jiawei, Zheng Xiaoting, Zhang Gaoyan, Cheng Zhikun, Liu Yinuo, Zhang Lei, Zhang Jiqian, Liu Xuesheng, Yang Zhilai
Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230022, China.
Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui Province, China.
Transl Psychiatry. 2025 Jun 17;15(1):203. doi: 10.1038/s41398-025-03417-0.
Post-traumatic stress disorder (PTSD) is a common disorder in clinical practice, characterized by various manifestations, with fear extinction dysfunction being a typical one. Postoperative persistent pain, a form of chronic pain following surgical procedures, significantly affects patients' quality of life. Clinical studies have demonstrated the comorbidity between chronic pain and PTSD; however, the molecular mechanisms underlying this comorbidity remain unclear. Researches have shown that brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate glutamate receptors (NMDARs) are crucial in fear extinction dysfunction. Thus, we established a skin/muscle incision and retraction (SMIR) mice model to explore the roles of hippocampal NMDARs and BDNF signaling pathways in fear extinction following postoperative persistent pain. We found that SMIR mice exhibited contextual fear extinction dysfunction, potentially caused by a down-regulated NMDARs/ERK/CREB/BDNF signaling pathway and impaired synaptic plasticity in the hippocampus. Hippocampal injection of the NMDARs agonist NMDA promoted extinction learning and retrieval of extinction memory, activating the NMDARs/ERK/CREB/BDNF signaling pathway, and restoring lost dendritic spines. Simultaneous hippocampal administration of NMDA and the TrkB inhibitor ANA-12 promoted the learning process of fear extinction without enhancing the retrieval of extinction memory, while re-inducing dendritic spine loss. In summary, we conclude that postoperative persistent pain impairs synaptic plasticity by downregulating the NMDARs/ERK/CREB/BDNF signaling pathway, thereby inducing contextual fear extinction dysfunction. These findings may partially explain the mechanisms underlying the comorbidity between chronic pain and PTSD.
创伤后应激障碍（PTSD）是临床实践中一种常见的疾病，具有多种表现形式，恐惧消退功能障碍是其典型表现之一。术后持续性疼痛是外科手术后慢性疼痛的一种形式，严重影响患者的生活质量。临床研究已经证实慢性疼痛与创伤后应激障碍之间存在共病现象；然而，这种共病现象背后的分子机制仍不清楚。研究表明，脑源性神经营养因子（BDNF）和N-甲基-D-天冬氨酸谷氨酸受体（NMDARs）在恐惧消退功能障碍中起关键作用。因此，我们建立了皮肤/肌肉切开和牵拉（SMIR）小鼠模型，以探讨海马NMDARs和BDNF信号通路在术后持续性疼痛后恐惧消退中的作用。我们发现，SMIR小鼠表现出情境性恐惧消退功能障碍，这可能是由于NMDARs/ERK/CREB/BDNF信号通路下调以及海马突触可塑性受损所致。海马注射NMDARs激动剂NMDA可促进消退学习和消退记忆的恢复，激活NMDARs/ERK/CREB/BDNF信号通路，并恢复丢失的树突棘。同时海马给予NMDA和TrkB抑制剂ANA-12可促进恐惧消退的学习过程，但不增强消退记忆的恢复，同时再次诱导树突棘丢失。总之，我们得出结论，术后持续性疼痛通过下调NMDARs/ERK/CREB/BDNF信号通路损害突触可塑性，从而诱导情境性恐惧消退功能障碍。这些发现可能部分解释了慢性疼痛与创伤后应激障碍共病现象背后的机制。
